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Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR(T790M)-negative but EGFR(G724S)-positive subclones and osimertinib resistance. We dem...

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Autores principales: Fassunke, Jana, Müller, Fabienne, Keul, Marina, Michels, Sebastian, Dammert, Marcel A., Schmitt, Anna, Plenker, Dennis, Lategahn, Jonas, Heydt, Carina, Brägelmann, Johannes, Tumbrink, Hannah L., Alber, Yannic, Klein, Sebastian, Heimsoeth, Alena, Dahmen, Ilona, Fischer, Rieke N., Scheffler, Matthias, Ihle, Michaela A., Priesner, Vanessa, Scheel, Andreas H., Wagener, Svenja, Kron, Anna, Frank, Konrad, Garbert, Katia, Persigehl, Thorsten, Püsken, Michael, Haneder, Stefan, Schaaf, Bernhard, Rodermann, Ernst, Engel-Riedel, Walburga, Felip, Enriqueta, Smit, Egbert F., Merkelbach-Bruse, Sabine, Reinhardt, H. Christian, Kast, Stefan M., Wolf, Jürgen, Rauh, Daniel, Büttner, Reinhard, Sos, Martin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220297/
https://www.ncbi.nlm.nih.gov/pubmed/30405134
http://dx.doi.org/10.1038/s41467-018-07078-0
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author Fassunke, Jana
Müller, Fabienne
Keul, Marina
Michels, Sebastian
Dammert, Marcel A.
Schmitt, Anna
Plenker, Dennis
Lategahn, Jonas
Heydt, Carina
Brägelmann, Johannes
Tumbrink, Hannah L.
Alber, Yannic
Klein, Sebastian
Heimsoeth, Alena
Dahmen, Ilona
Fischer, Rieke N.
Scheffler, Matthias
Ihle, Michaela A.
Priesner, Vanessa
Scheel, Andreas H.
Wagener, Svenja
Kron, Anna
Frank, Konrad
Garbert, Katia
Persigehl, Thorsten
Püsken, Michael
Haneder, Stefan
Schaaf, Bernhard
Rodermann, Ernst
Engel-Riedel, Walburga
Felip, Enriqueta
Smit, Egbert F.
Merkelbach-Bruse, Sabine
Reinhardt, H. Christian
Kast, Stefan M.
Wolf, Jürgen
Rauh, Daniel
Büttner, Reinhard
Sos, Martin L.
author_facet Fassunke, Jana
Müller, Fabienne
Keul, Marina
Michels, Sebastian
Dammert, Marcel A.
Schmitt, Anna
Plenker, Dennis
Lategahn, Jonas
Heydt, Carina
Brägelmann, Johannes
Tumbrink, Hannah L.
Alber, Yannic
Klein, Sebastian
Heimsoeth, Alena
Dahmen, Ilona
Fischer, Rieke N.
Scheffler, Matthias
Ihle, Michaela A.
Priesner, Vanessa
Scheel, Andreas H.
Wagener, Svenja
Kron, Anna
Frank, Konrad
Garbert, Katia
Persigehl, Thorsten
Püsken, Michael
Haneder, Stefan
Schaaf, Bernhard
Rodermann, Ernst
Engel-Riedel, Walburga
Felip, Enriqueta
Smit, Egbert F.
Merkelbach-Bruse, Sabine
Reinhardt, H. Christian
Kast, Stefan M.
Wolf, Jürgen
Rauh, Daniel
Büttner, Reinhard
Sos, Martin L.
author_sort Fassunke, Jana
collection PubMed
description The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR(T790M)-negative but EGFR(G724S)-positive subclones and osimertinib resistance. We demonstrate that EGFR(G724S) limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR(G724S) mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFR(G724S)-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR(G724S)-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR(G724S)-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
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spelling pubmed-62202972018-11-08 Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors Fassunke, Jana Müller, Fabienne Keul, Marina Michels, Sebastian Dammert, Marcel A. Schmitt, Anna Plenker, Dennis Lategahn, Jonas Heydt, Carina Brägelmann, Johannes Tumbrink, Hannah L. Alber, Yannic Klein, Sebastian Heimsoeth, Alena Dahmen, Ilona Fischer, Rieke N. Scheffler, Matthias Ihle, Michaela A. Priesner, Vanessa Scheel, Andreas H. Wagener, Svenja Kron, Anna Frank, Konrad Garbert, Katia Persigehl, Thorsten Püsken, Michael Haneder, Stefan Schaaf, Bernhard Rodermann, Ernst Engel-Riedel, Walburga Felip, Enriqueta Smit, Egbert F. Merkelbach-Bruse, Sabine Reinhardt, H. Christian Kast, Stefan M. Wolf, Jürgen Rauh, Daniel Büttner, Reinhard Sos, Martin L. Nat Commun Article The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR(T790M)-negative but EGFR(G724S)-positive subclones and osimertinib resistance. We demonstrate that EGFR(G724S) limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR(G724S) mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFR(G724S)-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR(G724S)-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR(G724S)-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors. Nature Publishing Group UK 2018-11-07 /pmc/articles/PMC6220297/ /pubmed/30405134 http://dx.doi.org/10.1038/s41467-018-07078-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fassunke, Jana
Müller, Fabienne
Keul, Marina
Michels, Sebastian
Dammert, Marcel A.
Schmitt, Anna
Plenker, Dennis
Lategahn, Jonas
Heydt, Carina
Brägelmann, Johannes
Tumbrink, Hannah L.
Alber, Yannic
Klein, Sebastian
Heimsoeth, Alena
Dahmen, Ilona
Fischer, Rieke N.
Scheffler, Matthias
Ihle, Michaela A.
Priesner, Vanessa
Scheel, Andreas H.
Wagener, Svenja
Kron, Anna
Frank, Konrad
Garbert, Katia
Persigehl, Thorsten
Püsken, Michael
Haneder, Stefan
Schaaf, Bernhard
Rodermann, Ernst
Engel-Riedel, Walburga
Felip, Enriqueta
Smit, Egbert F.
Merkelbach-Bruse, Sabine
Reinhardt, H. Christian
Kast, Stefan M.
Wolf, Jürgen
Rauh, Daniel
Büttner, Reinhard
Sos, Martin L.
Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title_full Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title_fullStr Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title_full_unstemmed Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title_short Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
title_sort overcoming egfr(g724s)-mediated osimertinib resistance through unique binding characteristics of second-generation egfr inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220297/
https://www.ncbi.nlm.nih.gov/pubmed/30405134
http://dx.doi.org/10.1038/s41467-018-07078-0
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